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ABSTRACT: Pharmacological activation of LRH-1/NR5A2 triggers an anti-inflammatory phenotypic switch in immune cells from individuals with type 1 diabetes and improves human islet engraftment/function

PROVIDER: PRJNA1017470 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26060946_1.fastq.gz	Fastqsanger.gz
	SRR26060946_2.fastq.gz	Fastqsanger.gz
	SRR26060947_1.fastq.gz	Fastqsanger.gz
	SRR26060947_2.fastq.gz	Fastqsanger.gz
	SRR26060948_1.fastq.gz	Fastqsanger.gz

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Pharmacological activation of LRH-1/NR5A2 triggers an anti-inflammatory phenotypic switch in immune cells from individuals with type 1 diabetes and improves human islet engraftment/function

Project description:The intricate aetiology of type 1 diabetes mellitus (T1DM) implicating a detrimental cross talk between immune cells and insulin producing -cells leading to their destruction has stumped the development of effective disease modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can revert hyperglycemia in pre-clinical mouse models of T1DM by attenuating the autoimmune attack coupled to -cell survival/regeneration, prompt us to investigate whether LRH-1/NR5A2-mediated immune tolerization could be achieved in individuals with T1DM and improve islet survival and function subsequent to xenotransplantation. We found that LRH-1/NR5A2 activation using the agonist BL001 blunted the pro-inflammatory genetic signature and cytokine secretome of both monocyte-derived macrophages (MDM1) and mature dendritic cells (mDCs) from individuals with T1DM. Mechanistically, mitohormesis was induced in MDM1 restricting pro-inflammation propagation while mitochondria turnover was increased in mDCs assisting transit towards a tolerogenic phenotype. BL001 treatment also increased T-regulatory cells within the T-cell subpopulation. BL001-treated MDM1, mDCs or T-cells impeded T-effector cell expansion. Engraftment and function of human islets transplanted into hyperglycemic immunocompetent mice was enhanced by BL001 treatment leading to improved glycemia. Collectively, LRH-1/NR5A2 agonism fosters a coordinated re-programming of T1DM immune cells from a pro- to an anti-inflammatory/tolerizing phenotype empowering them to repress cytotoxic T-cell proliferation and facilitates islet engraftment and function after transplantation. Our finding demonstrate the feasibility of re-establishing human immune tolerance within a pro-inflammatory environment, rather than suppression, opening an unprecedent pharmacological therapeutic venue for T1DM.

2025-04-09 | PXD045222 | Pride

Pharmacological activation of LRH-1/NR5A2 triggers an anti-inflammatory phenotypic switch in immune cells from individuals with type 1 diabetes and improves human islet engraftment/function

Project description:The intricate aetiology of type 1 diabetes mellitus (T1DM) implicating a detrimental cross talk between immune cells and insulin producing b-cells leading to their destruction has stumped the development of effective disease modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can revert hyperglycemia in pre-clinical mouse models of T1DM by attenuating the autoimmune attack coupled to b-cell survival/regeneration, prompt us to investigate whether LRH-1/NR5A2-mediated immune tolerization could be achieved in individuals with T1DM and improve islet survival and function subsequent to xenotransplantation. We found that LRH-1/NR5A2 activation using the agonist BL001 blunted the pro-inflammatory genetic signature and cytokine secretome of both monocyte-derived macrophages (MDM1) and mature dendritic cells (mDCs) from individuals with T1DM. Mechanistically, mitohormesis was induced in MDM1 restricting pro-inflammation propagation while mitochondria turnover was increased in mDCs assisting transit towards a tolerogenic phenotype. BL001 treatment also increased T-regulatory cells within the T-cell subpopulation. BL001-treated MDM1, mDCs or T-cells impeded T-effector cell expansion. Engraftment and function of human islets transplanted into hyperglycemic immunocompetent mice was enhanced by BL001 treatment leading to improved glycemia. Collectively, LRH-1/NR5A2 agonism fosters a coordinated re-programming of T1DM immune cells from a pro- to an anti-inflammatory/tolerizing phenotype empowering them to repress cytotoxic T-cell proliferation and facilitates islet engraftment and function after transplantation. Our finding demonstrate the feasibility of re-establishing human immune tolerance within a pro-inflammatory environment, rather than suppression, opening an unprecedent pharmacological therapeutic venue for T1DM

2025-04-09 | PXD053517 | Pride

Pharmacological activation of LRH-1/NR5A2 triggers an anti-inflammatory phenotypic switch in immune cells from individuals with type 1 diabetes and improves human islet engraftment/function

Project description:Pharmacological activation of LRH-1/NR5A2 triggers an anti-inflammatory phenotypic switch in immune cells from individuals with type 1 diabetes and improves human islet engraftment/function

| PRJEB65863 | ENA

LRH-1/NR5A2 induces M1 to M2 macrophage phenotypic switch

Project description:LRH-1/NR5A2 induces M1 to M2 macrophage phenotypic switch

| PRJNA412367 | ENA

LRH-1 Mitigates Intestinal Inflammatory Disease by Maintaining Epithelial Homeostasis and Cell Survival

Project description:We report the gene expression changes in murine small intestinal organoids following deletion of LRH-1 (NR5A2) and humanization by expression of human LRH-1 in mouse LRH-1 knockout organoids.

2018-07-04 | GSE116563 | GEO

LRH1 silencing inhibits human colon cancer growth.

Project description:This study was undertaken to better determine the function of LRH-1 (NR5A2) in the colorectal cancers (CRC) through inducible shRNA-mediated knockdown within well-established CRC cell line Caco-2 Our work is the first to demonstrate that silencing of LRH-1 in established human CRC cell lines impairs proliferation though G0/G1 phase prolongation, and alteration in diverse cellular pathways consistent with the critical role of LRH-1 in CRC.

2015-02-24 | GSE64695 | GEO

A Role for Orphan Nuclear Receptor Liver Receptor Homolog-1 (LRH-1, NR5A2) in Primordial Follicle Activation

Project description:The ovarian reserve of follicles comprises all oocytes for lifetime fertility and is depleted by progressive activation. The orphan nuclear receptor liver receptor homolog 1 (LRH-1; Nr5a2) is essential for ovulation, but its role in the early stages of follicular development is not known. We therefore developed a model of conditional depletion of LRH-1 from early postnatal ovaries (postnatal day 4) and performed RNAsequencing to identify LRH-1 regulated genes during the earliest stages of follicular activation.

2022-10-24 | GSE216392 | GEO

Genome-wide mapping of Nr5a2 in mouse embryonic stem cells

Project description:Nr5a2 (also known as liver receptor homolog-1, Lrh-1) has been shown to bind both the proximal enhancer and proximal promoter regions of Pou5f1 and regulate Pou5f1 in the epiblast stage of mouse embryonic development (Gu et al., 2005). Nr5a2-null embryos display a loss of Oct4 expression in the epiblasts (Gu et al., 2005) and die between E6.5 and E7.5 (Gu et al., 2005; Pare et al., 2004). To identify the targets of Nr5a2, we generated a stable ES cell-line that expresses HA-tagged Nr5a2. Anti-HA antibody was used to immunoprecipitate HA-Nr5a2 for ChIP-seq analysis. Keywords: Transcription factor binding sites To identify the binding sites of Nr5a2, we generated a stable ES cell-line that expresses HA-tagged Nr5a2. Anti-HA antibody was used to immunoprecipitate HA-Nr5a2.

2010-01-22 | E-GEOD-19019 | biostudies-arrayexpress

Genome-wide mapping of Nr5a2 in mouse embryonic stem cells

2010-01-22 | GSE19019 | GEO

LRH-1 governs vital transcriptional programs in endocrine sensitive and resistant breast cancer cells: Expression profiling

Project description:Tumor characteristics are decisive in the determination of treatment strategy for breast cancer patients. Patients with estrogen receptor-α (ERα) positive breast cancer can benefit from long-term hormonal treatment. Nonetheless, the majority of patients will develop resistance to these therapies. Here, we investigated the role of the liver receptor homolog-1 (LRH-1, NR5A2) in anti-estrogen (AE) sensitive and resistant breast cancer cells. We identified genome-wide LRH-1 binding sites using ChIP-seq, uncovering preferential binding to regions distal to transcriptional start sites (TSS). We further characterized these LRH-1 binding sites by integrating overlapping layers of specific chromatin marks, revealing that many LRH-1 binding sites are active and could be involved in long-range enhancer-promoter looping. Combined with transcriptome analysis of LRH-1 depleted cells, these results show that LRH-1 regulates specific subsets of genes involved in cell proliferation in AE-sensitive and AE-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with signature of poor outcome breast cancer tumors in vivo. Herein report the genome-wide location and molecular function of LRH-1 in breast cancer cells and reveal its therapeutic potential for the treatment of breast cancers, notably for tumors resistant to treatments currently used in therapies.

2014-02-27 | GSE54891 | GEO

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